Granular composition for oral administration

ABSTRACT

The present invention relates to a granular composition for oral suspension characterized by the presence of an insoluble resin and a silica gel.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 of PCT/EP2016/068022, filed Jul. 28, 2016,which claims the benefit of priority from U.S. patent application Ser.No. 14/829,912, filed Aug. 19, 2015, the contents of each of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a granular composition for oralsuspension characterized by the presence of an insoluble resin and asilica gel.

BACKGROUND OF THE INVENTION

It is known that insoluble resins, such as Sevelamer, Cholestyramine orColesevelam, are extremely helpful in treating several pathologies suchas hypercholesterolemia (acting as bile acid sequestrants) orhyperphosphataemia (acting as phosphate binding drug) in patients withchronic kidney diseases.

These insoluble resins are all characterized by:

-   -   elevated molecular weight;    -   low or very low solubility, or insolubility;    -   elevated therapeutically dosage to be administered;    -   elevated electrostatic charge;    -   low flowability.

These characteristics cause serious issues in formulating granularcompositions for oral suspension to be filled in a container, such assachets or cans.

In fact, due to these negative properties, the Health Authorities (suchas the Food and Drug Administration) did not authorize to fillcontainers (sachets or cans) with said insoluble resins over the limitsof ±5% of the target weight for each container. Usually, in order tosolve the difficulties related to the low flowability of the granularcomposition and to the poor uniformity content of the containers, theformulators are obliged to use special dosage equipments.

However, the use of special dosage equipments often do not solve theseproblems because of the poor wettability and floating on the surface ofthe liquid—thus remaining immiscible—of the granular composition, causedby the electrostatic charges of said granular composition.

Thus, granular compositions for oral administration comprising suchinsoluble resins in higher amount for each container and with betterflowability and uniformity are needed. Silica gels are usually used inseveral industrial applications, and particularly in pharmaceuticalfield, because of their considerable absorbing power, and their enormoussurface area.

Surprisingly, it has been found that the granular compositionscomprising insoluble resins, such as Sevelamer, Cholestyramine orColesevelam, lose all the negative characteristics mentioned-above whena certain amount of silica gel, preferably highly porous silica gelhaving a mesoporous structure such as Syloid® XDP or Syloid® FP, isadded to said granular compositions. thus allowing a better wettabilityof the insoluble granular composition, and the preparation of reliabledosage forms. In addition, if such silica gels are used in thecompositions of the present invention an higher amount of insolubleresins for each container can be used.

SUMMARY OF THE INVENTION

The present invention refers to a granular composition for oralsuspension characterized by the presence of an insoluble resin and asilica gel.

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the present invention, the expression “porosity of amaterial” refers to the % ratio between the volume of the pores and thetotal volume of the considered material.

For the purpose of the present invention, the expression “highly porousmaterial” refers to a material which has a porosity higher than 20%,preferably higher than 40%, even more preferably higher than 60%. In apreferred embodiment, the highly porous material has a porositycomprised in the range of 60-95%.

For the purpose of the present invention the expression “mesoporousmaterial” refers to a material with a porous diameter size comprised inthe range of 2-50 nm.

Silica gels (such as Syloie), which are characterized by a high porosityand a mesoporous structure, are widely used within the pharmaceuticalindustry as excipients and processing aids.

The properties and the characteristics of such silica gels are known inthe literature. They are referenced by FDA's as inactive ingredients andare specifically cited in numerous drug patents due to their uniquemorphology and properties that improve the handling, adsorption, anddissolution of many pharmaceuticals. In fact, the combined adsorptioncapacity, porosity, particle size, and greater internal surface areaallow them to provide several benefits simultaneously that can help tominimize the number of excipients required, to expedite manufacturing,and to improve efficacy of the final dosage form.

Examples of commercial Syloid® to be used according to the presentinvention are Syloid®XDP-3050, XDP-3150, and Syloid® FP.

Syloid® XDP usually refers to silica carriers consisting of an optimizedmesoporous material, engineered for transforming liquids to free flowingsolids, particularly oily actives and lipid-based systems. Generallyspeaking, such carriers lead to several advantages. such as transformingliquids to easy to handle solids, improving bioavailability of oilyactives, increasing API loading in solid dosage forms; quick releasingof API.

Syloid® FP are usually used in the pharmaceutical applications aseffective desiccants to increase the stability of moisture-sensitiveAPIs, as efficient conditioners for powder formulations used insuspensions, as capillary wetting agents for better release anddisintegration.

The present invention refers to a granular composition for oraladministration comprising a non soluble resin and a silica gel selectedfrom the group consisting of: Syloid®FP and Syloid®XDP. More preferably,the silica gel is Syloid®XDP. Even more preferably, Syloid®® XDP isSyloid® XDP-3050 or Syloid® XDP-3150. Syloid®XDP-3050 is preferred.

Preferably, the silica gel is Syloid®FP in the range of 0.1%-5% (w/w)

Preferably, the silica gel is Syloid®XDP in the range of 0.4%-1.0%(w/w).

Preferably, the insoluble resin of the granular composition of thepresent invention is selected from the group consisting of: Sevelamercarbonate. Sevelamer hydrochloride, Cholestyramine and Colesevelamhydrochloride. Sevelamer carbonate is preferred.

In a preferred embodiment, the granular composition of the presentinvention, further comprises a flavour, when the insoluble resin isSevelamer carbonate.

More preferably, the flavour is selected from the group consisting of:citrus flavour, berry flavour, peach flavour, apricot flavour, mintflavour, anise flavour, grape flavour, cherry flavour and a mixturethereof. Citrus flavour is preferred.

Preferably, the granular composition of the present invention furthercomprises an artificial sweetener when citrus flavor is used. Preferablythe artificial sweetener is aspartame.

Surprisingly, it has been found that the silica gel disclosed in thepresent invention advantageously reduces the electrostatic charges ofthe granular composition; therefore, the wettability of the insolublegranular composition is increased, thus allowing the preparation ofreliable dosage forms. In fact, by using the silica gel disclosed hereinthe dispersion in a liquid, when orally administered, is facilitated.

In addition, another advantage of the present invention is that thegranular composition here disclosed can be easily filled in sachetsusing a traditional dosing machine filled by gravity, and not thespecial equipments usually used and known in the state of the art. thusproducing sachets with a Variation Coefficient (CV) of no more than(NMT) 3% or filled in cans with CV of NMT 3%.

Moreover, when bulk in water, the granular composition of the presentinvention rapidly forms a jelly suspension, thus advantageously allowingthe correct administration of the medicament.

The following examples better illustrate the present invention withoutlimiting it. Please note that, for the purposes of the presentinvention, the meaning of the following acronyms is reported below:

-   -   “CV” refers to “Variation Coefficient”;    -   “PASS” refers to “Comply with the specifications”;    -   “MT” refers to “More Than”;    -   “TYPICAL” means that the flavour and taste are typical of the        selected flavour.

Example 1

The following compositions A-S have been prepared by pouring theingredients listed in the Tables below:

A B C D E F mg % mg % mg % mg % mg % mg % Sevelamer 2400.00 93.312400.00 93.31 2400.00 93.13 2400 92.73 2400 91.50 2400 93.31 carbonateCitrus flavour 66.60 2.54 66.60 2.54 66.60 2.58 66.66 2.57 66.60 2.5466.60 2.54 Propylen glycol 60.00 2.32 60.00 2.32 60.00 2.33 60.00 2.3260.00 2.29 60.00 2.32 alginate NaCl 40.00 1.54 40.00 1.54 40.00 1.5540.00 1.55 40.00 1.52 40.00 1.54 Syloid XDP-3050 23.40 0.91 — — — — 2.300.10 128.60 5 — — Syloid XDP-3150 — —                 23.40 0.91 AerosilV200 — — 23.40 0.91 — — — — — — — Sucralose 10.00 0.38 10.00 0.38 10.000.39 10 0.39 10.00 0.38 10.00 0.38 Total 2600 100 2600 100 2577 100 2579100 2705 100 2600 100 G H I L M mg % mg % mg % mg % mg % Cholestyramine4000 70.17 4000 70.17 4000 70.17 4000 70.17 4000 70.17 Propylen glycol250 4.39 250 4.39 250 4.39 250 4.39 250 4.39 alginate Fructose 125522.02 1255 22.02 1300 22.81 1294 22.41 1045 21.23 Citrus Flavour 80 1.4080 1.40 80 1.40 80 1.40 80 1.40 Citric acid 50 0.88 50 0.88 50 0.88 500.88 50 0.88 Syloid XDP-3050 45 0.79 — — — — 6 0.10 285 5.00 SyloidXDP-3150 — — — — — — — — — Aerosil V200 — — 45 0.79 — — — — — Aspartame20 0.35 20 0.35 20 0.35 20 0.35 20 0.35 Total 5700 100 5700 100 5700 1005700 100 5700 100 N O P Q R S mg % mg % mg % mg % mg % mg %Cholestyramine 4000 44.44 4000 44.44 4000 44.44 4000 44.44 4000 44.444000 44.44 Propylen glycol 90 1.00 90 1.00 90 1.00 90 1.00 90 1.00 901.00 alginate Saccharose 4640 51.55 4640 51.55 4685 52.06 4676 51.804235 47.05 4640 51.55 Citrus Flavour 180 2.00 180 2.00 180 2.00 180 2.00180 2.00 180 2.00 Citric acid 45 0.50 45 0.50 45 0.50 45 0.50 45 0.50 450.50 Syloid XDP-3050 45 0.50 — — — — 9.00 0.10 450 5.00 — — SyloidXDP-3150 — — — — — — — — — — 45 0.5 Aerosil V200 — — 45 0.50 — — — — — —— — Total 9000 100 9000 100 9000 100 9000 100 9000 100 9000 100

The resulting mix were blended for 10 minutes and were collected in acontainer.

The mix were then characterized from physical point of view.

Physical characteristics of the mix Bulk Tapped density densityComposition Flowability [g/ml] [g/ml] Appearance A 33.7° 0.6 0.7Yellowish powder B Not measurable 0.4 0.7 Yellowish powder C Notmeasurable 0.4 0.7 Yellowish powder D 36.5° 0.6 0.7 Yellowish powder E32.8° 0.6 0.7 Yellowish powder F 33.6° 0.6 0.7 Yellowish powder G 34.3°0.7 0.9 Almost white powder H Not measurable 0.6 0.9 Almost white powderI Not measurable 0.4 0.7 Yellowish powder L 37.5° 0.7 0.9 Almost whitepowder M 32.5° 0.7 0.9 Almost white powder N 31.2° 0.8 0.9 Almost whitepowder O 42.0° 0.8 1.0 Almost white powder P Not workable 0.7 0.9 Almostwhite powder flowability Q 34.6° 0.7 0.9 Almost white powder R 30.5° 0.70.9 Almost white powder S 31.2° 0.8 0.9 Almost white powder

The mix was then filled in a Marchesini RC 600 filling machine equippedwith a dosing device filled by gravity, and the product was filled inAluminium-Aluminium sachets in reason of 9.0 g each, or alternatively ina composite can, containing 239.4 or 378 g of granular and dispensedwith a spoon corresponding to 5.7 g or 9.0 g of mixture.

Physical characteristics of the sachet/mix Mean CV Tightness weight [mg][%] of sachets A 2600  ±2.5 PASS B Not fillable NA NA C Not fillable NANA D 2588 ±10 PASS E 2705  ±2.5 PASS F 2600  ±2.5 PASS G 5700  ±2.5 PASSH Not fillable NA NA I Not fillable NA NA L 5700  10 PASS M 5700  ±2.5PASS N 9000  ±2.5 PASS O 9000 ±10 PASS P 9000 ±10 PASS Q 9000  ±2.5 PASSR 9000  ±2.5 PASS S 9000  ±2.5 PASS

A sachet comprising formula selected among A-S was then suspended in 60ml of tap water; the characteristics of the derived suspensions arereported in the Table below

Characteristics of the suspension Time of residence on the top of theAppearance of the Appearance of the suspension/ suspension after 1suspension after 5 Taste of the water minute minutes suspension A 20″Homogeneous, cloudy Slightly precipitated Typical of flavor B MT 10′Product floating on the Product floating on the Typical of flavor andsurface of water surface of water sandy C MT 10′ Product floating on theProduct floating on the Typical of flavor c surface of water surface ofwater and sandy D 50″ Homogeneous, cloudy Almost precipitated Typical offlavor E 20″ Totally sediment Totally sediment Typical of flavor F MT10″ Homogeneous, cloudy Slightly precipitated Typical of flavor G 10″Homogeneous, cloudy Slightly precipitated Typical of flavor H MT 10′Product floating on the Product floating on the Typical of flavor andsurface of water surface of water sandy I MT 10″ Product floating on theProduct floating on the Typical of flavor and surface of water surfaceof water sandy L 20″ Homogeneous, cloudy Almosts edimented Typical offlavor M 10″ Totally sediment Totally sediment Typical of flavor N 10″Homogeneous, cloudy Slightly precipitated Typical of flavor O 40″Slightly precipitated Almost precipitated Typical of flavor P 40″Slightly precipitated Almost precipitated Typical of flavor Q 20″Homogeneous, cloudy Slightly sedimented Typical of flavor R MT 10′Product floating on the Products floating on the Typical of flavorsurface of water surface of water S 10″ Homogeneous, cloudy Slightlyprecipitated Typical of flavor

From the data reported above, it is thus clear that both Syloid®XDP-3050 and Syloid® XDP-3150 are suitable for the present invention;Syloid® XDP-3050 is preferred.

By making a comparison between the suspensions comprising the followingcompositions:

-   -   A and B,    -   G and H. and    -   N and O;

where in compositions A, G and N Syloid® XDP-3050 has been used, and incompositions B, H and O AerosilV200 has been used, the suspensioncomprising Syloid®XDP-3050 showed an homogeneous and cloudy appearanceafter 1 minute, whereas in the suspensions comprising a silica geldifferent from Syloid®XDP-3050 the product floated on the surface of thewater already after 1 minute. A similar result has been obtained for thesuspensions where no silica gel is added to the compositions. In fact,for the compositions C, I and P, already after 1 minute the productfloated on the surface of water, thus causing the problems informulating granular compositions for oral suspension to be filled in acontainer mentioned above. The use of Siloyd®XDP-3050 advantageouslyovercomes these issues.

Moreover, a significant increase of Syloid® XDP-3050 (around 5%) in thecomposition, did not improve the physical parameters, but increased thesedimentation speed (see the compositions A and E, G and M, and N and R,where the appearance of the suspension after 1 minute of compositions A,G and N is “Homogeneous. cloudy”, whereas for compositions E, M and R is“Totally sediment” or “Product floating on the surface of the water”).

What is claimed is:
 1. A granular composition for oral administrationcomprising a non soluble resin and a highly porous silica gel having amesoporous structure, wherein the highly porous silica gel is in therange of 0.1%-5% (w/w).
 2. The granular composition according to claim1, wherein the highly porous silica gel is in the range of 0.4%-1.0%(w/w).
 3. The granular composition according to claim 1, wherein the nonsoluble resin is selected from the group consisting of: Sevelamercarbonate, Sevelamer hydrochloride, Cholestyramine and Colesevelamhydrochloride.
 4. The granular composition according to claim 3, whereinthe non soluble resin is Sevelamer carbonate, and wherein said granularcomposition further comprises a flavor.
 5. The granular compositionaccording to claim 4, wherein the flavor is selected from the groupconsisting of: citrus flavor, berry flavor, peach flavor, apricotflavor, mint flavor, anise flavor, grape flavor, cherry flavor and amixture thereof.
 6. The granular composition according to claim 4,wherein the flavor is citrus flavor, and wherein the granularcomposition further comprises an artificial sweetener.
 7. The granularcomposition according to claim 6, wherein the artificial sweetener isaspartame.
 8. The granular composition according to claim 6, wherein theartificial sweetener is sucralose.